ISS: Engineering Stem Cell-Derived Cardiac Microtissues with Metabolic Regulators in Space to Promote Cardiomyocyte Maturation

ISS：在太空中利用代谢调节剂改造干细胞衍生的心脏微组织以促进心肌细胞成熟

• 批准号: 1926387
• 负责人: Chunhui Xu
• 金额: $ 40万
• 依托单位: Emory University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1926387&HistoricalAwards=false
• 关键词: ISS; Engineering; Stem; Cell; Derived

Cardiac muscle cells generated from stem cells could be used to replace damaged cells in patients with heart disease, which is the leading cause of death in the United States. Scientists have also used these cells to study heart disease and drug responses. Currently, when scientists grow cardiac muscle cells in a dish, the characteristics of these cells look like the heart cells at the early developmental stage; their shape, size, and function resemble immature heart cells. Ideally, more mature cardiac muscle cells are needed in cardiac cell replacement therapy and the study of heart disease. Therefore, developing methods to accelerate the maturation of cardiac muscle cells is highly significant. The unique environment of the International Space Station (ISS) is known to provide beneficial effects on human cardiac precursors to help their growth and differentiation. In this project, the research team will investigate the maturation of stem cell-derived cardiac muscle cells by growing these cells in tissue-like structures in the ISS. The investigators also plan to develop a technology to promote cardiac muscle cell maturation in microtissues that are suitable for large-scale production, a requirement essential for translational research. This project also incorporates the training of young scientists and students and provides science-learning opportunities for kids in a local hospital in the Children's Healthcare of Atlanta system. The goal of this project is to establish a multipronged approach combining microgravity, tissue engineering and metabolic regulation to promote the maturation of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs). First, the investigators will optimize the design of tissue engineering and cell culture conditions in ground-based experiments by examining the effect of simulated microgravity, cell composition and metabolic regulation. Second, the hiPSC-CM microtissues will be cultured in the ISS. The experiments will be performed within a perfusion system that is suitable for suspension cell culture and has gas permeable membranes that allow sufficient gas exchange for cell growth. The cells will remain in the same culture units throughout the experiment and cell morphology will be monitored once a week utilizing an inverted phasecontrast microscope currently available at the ISS, and the imaging data will be transmitted for ground-based control and data retrieval. Following spaceflight, the researchers will investigate molecular and functional characteristics of the hiPSC-CMs. Exposure of hiPSC-CM microtissues to microgravity in space is expected to eliminate shear stress and consequently enhance cell-cell and cell-matrix interactions within multicellular architectures. Findings from this project will provide insights into the molecular regulation of accelerated hiPSC-CM maturation. Applying these insights to the research on earth could assist in the production of more mature hiPSC-CMs to enhance their potential application in regenerative medicine, the study of heart disease and drug development. (Project integration and operation on the ISS will be provided by the Center for the Advancement of Science in Space (CASIS) implementation partner, BioServe.)This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

由干细胞产生的心肌细胞可用于替代心脏病患者的受损细胞，心脏病是美国的主要死因。科学家们还利用这些细胞来研究心脏病和药物反应。目前，当科学家在培养皿中培养心肌细胞时，这些细胞的特征看起来像早期发育阶段的心脏细胞;它们的形状，大小和功能类似于未成熟的心脏细胞。理想情况下，在心脏细胞替代疗法和心脏病研究中需要更成熟的心肌细胞。因此，开发加速心肌细胞成熟的方法是非常重要的。众所周知，国际空间站（ISS）的独特环境对人类心脏前体细胞产生了有益的影响，有助于它们的生长和分化。在这个项目中，研究小组将通过在ISS中的组织样结构中培养这些细胞来研究干细胞衍生的心肌细胞的成熟。研究人员还计划开发一种技术，以促进适合大规模生产的微组织中的心肌细胞成熟，这是转化研究的必要条件。 该项目还包括对年轻科学家和学生的培训，并为亚特兰大儿童保健系统当地医院的儿童提供科学学习机会。 该项目的目标是建立一种多管齐下的方法，结合微重力，组织工程和代谢调控，以促进来自人类诱导多能干细胞（hiPSC-CM）的心肌细胞的成熟。首先，研究人员将通过检查模拟微重力，细胞组成和代谢调节的影响，优化组织工程和细胞培养条件的设计。其次，将在ISS中培养hiPSC-CM微组织。实验将在灌注系统中进行，该系统适用于悬浮细胞培养，并具有透气膜，可进行足够的气体交换以促进细胞生长。在整个实验过程中，细胞将保持在相同的培养单元中，将利用国际空间站现有的倒置相差显微镜每周监测一次细胞形态，并将传送成像数据用于地面控制和数据检索。 在太空飞行之后，研究人员将研究hiPSC-CM的分子和功能特征。hiPSC-CM微组织在太空中暴露于微重力下预计会消除剪切应力，从而增强多细胞结构内的细胞-细胞和细胞-基质相互作用。该项目的发现将为加速hiPSC-CM成熟的分子调控提供见解。 将这些见解应用于地球上的研究可以帮助生产更成熟的hiPSC-CM，以提高其在再生医学，心脏病研究和药物开发中的潜在应用。（国际空间站上的项目集成和操作将由空间科学促进中心（CASIS）的执行伙伴BioServe提供。该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估的支持。

项目成果

Machine learning identifies abnormal Ca(2+) transients in human induced pluripotent stem cell-derived cardiomyocytes.

• DOI: 10.1038/s41598-020-73801-x
• 发表时间: 2020-10-12
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Hwang H;Liu R;Maxwell JT;Yang J;Xu C
• 通讯作者: Xu C

Space microgravity increases expression of genes associated with proliferation and differentiation in human cardiac spheres.

• DOI: 10.1038/s41526-023-00336-6
• 发表时间: 2023-12-09
• 期刊: NPJ MICROGRAVITY
• 影响因子: 5.1
• 作者: Hwang, Hyun;Rampoldi, Antonio;Forghani, Parvin;Li, Dong;Fite, Jordan;Boland, Gene;Maher, Kevin;Xu, Chunhui
• 通讯作者: Xu, Chunhui

Chronic ethanol exposure induces mitochondrial dysfunction and alters gene expression and metabolism in human cardiac spheroids

• DOI: 10.1111/acer.15026
• 发表时间: 2023-02-17
• 期刊: ALCOHOL-CLINICAL AND EXPERIMENTAL RESEARCH
• 作者: Hwang，Hyun;Liu，Rui;Xu，Chunhui
• 通讯作者: Xu，Chunhui

AMPK activator-treated human cardiac spheres enhance maturation and enable pathological modeling.

• DOI: 10.1186/s13287-023-03554-7
• 发表时间: 2023-11-08
• 期刊: Stem cell research & therapy
• 影响因子: 7.5

Space microgravity improves proliferation of human iPSC-derived cardiomyocytes.

太空微重力可改善人类 iPSC 来源的心肌细胞的增殖。

• DOI: 10.1016/j.stemcr.2022.08.007
• 发表时间: 2022-10-11
• 期刊: STEM CELL REPORTS
• 影响因子: 5.9
• 作者: Rampoldi, Antonio;Forghani, Parvin;Li, Dong;Hwang, Hyun;Armand, Lawrence Christian;Fite, Jordan;Boland, Gene;Maxwell, Joshua;Maher, Kevin;Xu, Chunhui
• 通讯作者: Xu, Chunhui